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PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer

 Chan Kim  ;  Choong-Kun Lee  ;  Hong Jae Chon  ;  Joo Hoon Kim  ;  Hyung Soon Park  ;  Su Jin Heo  ;  Hyun Jeong Kim  ;  Tae Soo Kim  ;  Woo Sun Kwon  ;  Hyun Cheol Chung  ;  Sun Young Rha 
 Oncotarget, Vol.8(69) : 113494-113501, 2017 
Journal Title
Issue Date
HER2 ; PTEN ; gastric cancer ; resistance ; trastuzumab
Background: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results: Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index (<5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김주훈(Kim, Joo Hoon)
김태수(Kim, Tae Soo)
라선영(Rha, Sun Young) ORCID logo https://orcid.org/0000-0002-2512-4531
박형순(Park, Hyung Soon)
이충근(Lee, Choong Kun)
정현철(Chung, Hyun Cheol) ORCID logo https://orcid.org/0000-0002-0920-9471
허수진(Heo, Su Jin) ORCID logo https://orcid.org/0000-0002-0615-5869
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